Skin-Intrinsic Immunosuppressive Mesenchymal Stem Cells and aGVHD

皮肤固有免疫抑制间充质干细胞和 aGVHD

• 批准号: 10345441
• 负责人: NATASHA Y FRANK
• 金额: $ 43.35万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10345441
• 关键词: Acute Graft Versus Host Disease; Address; Affect; Allogeneic Bone Marrow Transplantation; Allogenic; Apoptosis; Attenuated; Biological Assay; Bone Marrow; Bone Marrow Cell Transplantation; Cell Communication; Cells; Cessation of life; Characteristics; Collaborations; Complement; Complication; Cutaneous; Cytokeratin; Cytokine Network Pathway; Data; Dendritic Cells; Dermal; Disease; Disease Progression; Epidermal Ridges; Epithelial; Epithelial Cells; Family member; Funding; Goals; Graft-Versus-Tumor Induction; Hair follicle structure; Home; Immune; Immune response; Immunophenotyping; Immunosuppression; Inflammatory; Laboratories; Lead; Life; Limb structure; Liver; Mediating; Mediator of activation protein; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Messenger RNA; Minor Histocompatibility Antigens; Modeling; Monitor; Morbidity - disease rate; Mucous Membrane; Multi-Drug Resistance; Mus; Organ; Organ Culture Techniques; Organ Transplantation; PD-1 pathway; PD-1/PD-L1; Pathology; Pathway interactions; Patients; Phenotype; Prevention; Proteins; RNA; Recovery; Research; Resistance; Resolution; Severity of illness; Site; Skin; Solid; Solid Neoplasm; Stem cell transplant; System; T cell response; T-Lymphocyte; TP53 gene; Therapeutic; Tissues; Validation; Work; Xenograft Model; base; cancer therapy; cytokine release syndrome; cytotoxic; design; digital; epithelial injury; epithelial stem cell; graft vs host disease; immune reconstitution; immunoregulation; in vivo; knockout gene; laser capture microdissection; leukemia treatment; leukemia/lymphoma; mouse model; novel therapeutic intervention; programmed cell death ligand 1; programmed cell death protein 1; skin disorder; spatiotemporal; stem cell biomarkers; stem cell engraftment; stem cell fate; stem cell function; stem cells; tissue injury

Project Summary/Abstract Acute graft-versus-host disease (aGVHD) is a major limiting complication of allogeneic stem cell transplantation for the treatment of leukemia/lymphoma and certain solid tumors. aGVHD occurs when T lymphocytes from donor bone marrow attack cells within the recipient that are critical to the function vital organs, namely skin, liver and gut. During the past three decades of research, Dr. Murphy’s laboratory has found that in skin and squamous mucosae, the first sites of effector-target cell interaction provoked by differences in minor histocompatibility antigens, involve T cells bearing Vb-specific markers that home selectively to epithelial rete ridges as well as the epithelial stem cell-rich bulge regions of murine hair follicles. This association results in death by apoptosis of adjacent epithelial cells that express the stem cell marker, cytokeratin 15. Systemic therapeutic inhibition of these effector limbs is riddled with problems that include collateral impact on immune reconstitution and blunting of graft-versus-tumor effects. However, we now know through discoveries made in collaboration with co-PIs of this proposal, Drs. Markus and Natasha Frank, that the skin and squamous mucosae harbor intrinsic cellular pathways capable of potent immunosuppression. Specifically, we have discovered a dermal dendritic cell that has stem cell characteristics, expresses the multidrug resistance transporter ABCB5, and also expresses PD-1. This cell has the ability to thwart T cell responses, including alloreactivity, and therefore holds significant but as yet unexplored promise as a skin- intrinsic pathway that may be leveraged to inhibit the tissue injury in aGVHD. In this proposal, Dr. Murphy and the Drs. Frank have combined forces to address the long-term objective of harnessing the skin’s intrinsic immunosuppressive capabilities to thwart aGVHD. The proposal’s specific objective is to determine the impact of PD-1-expressing immunosuppressive dermal mesenchymal stem cells on the earliest and most specific effector-target cell interactions responsible for aGVHD. To this end, we have proposed three specific aims: 1) to correlate spatiotemporal multiplex immune profiling with all aspects of disease morbidity and recovery in aGVHD; 2) to dissect ABCB5 dermal stem cell function in aGVHD and define PD-1/PD-L1-centered strategies for skin-intrinsic immunosuppression; and 3) to apply ABCB5+ dermal stem cell transplant strategies to influence aGVHD severity using spatiotemporal multiplex immune profiling as effector-target bioassay. The approaches involve state-of-the-art multiplex immunophenotyping of effector-target cell interactions that sensitively and specifically typify tissue injury in aGVHD, and leverage ABCB5 gene knockout and lineage tracing models in context of PD-L1 Ig administration and ABCB5+ stem cell engraftment. The rationale is that upon successful completion of this work, we will identify novel therapeutic approaches to the treatment and prevention of aGVHD skin and squamous mucosal pathology through manipulation of skin- intrinsic immunosuppressive pathways.

项目概要/摘要 急性移植物抗宿主病（aGVHD）是同种异体干细胞的主要限制性并发症 移植用于治疗白血病/淋巴瘤和某些实体瘤。当 T 时发生 aGVHD 来自供体骨髓的淋巴细胞会攻击受体内对生命功能至关重要的细胞 器官，即皮肤、肝脏和肠道。在过去三十年的研究中，墨菲博士的实验室已经 发现在皮肤和鳞状粘膜中，效应细胞与靶细胞相互作用的第一个位点是由 微小组织相容性抗原的差异，涉及带有 Vb 特异性标记的 T 细胞 选择性地作用于上皮网脊以及小鼠毛囊的上皮干细胞丰富的凸起区域。 这种关联导致表达干细胞标记的相邻上皮细胞凋亡而死亡， 细胞角蛋白 15。这些效应肢的全身治疗性抑制充满了问题，包括 对免疫重建和移植物抗肿瘤效应减弱的附带影响。然而，我们现在知道 通过与该提案的共同 PI 合作取得的发现，博士。马库斯和娜塔莎·弗兰克 皮肤和鳞状粘膜具有能够有效抑制免疫的内在细胞途径。 具体来说，我们发现了一种具有干细胞特征的真皮树突状细胞，表达 多药耐药转运蛋白 ABCB5，还表达 PD-1。该细胞具有阻止 T 细胞的能力 反应，包括同种异体反应，因此作为皮肤具有重要但尚未探索的前景。 可以利用内在途径来抑制 aGVHD 中的组织损伤。在这项提案中，墨菲博士和 博士们。弗兰克（Frank）联合力量来实现利用皮肤内在的长期目标 免疫抑制能力可阻止 aGVHD。该提案的具体目标是确定影响 表达PD-1的免疫抑制真皮间充质干细胞对最早和最特异的 效应器-靶细胞相互作用导致aGVHD。为此，我们提出了三个具体目标： 1) 将时空多重免疫分析与疾病发病率和恢复的各个方面联系起来 在aGVHD中； 2) 剖析 ABCB5 真皮干细胞在 aGVHD 中的功能并定义以 PD-1/PD-L1 为中心 皮肤内在免疫抑制策略； 3) 进行ABCB5+真皮干细胞移植 使用时空多重免疫分析作为效应目标影响 aGVHD 严重程度的策略 生物测定。这些方法涉及效应靶细胞的最先进的多重免疫表型分析 敏感且特异地表征 aGVHD 中组织损伤的相互作用，并利用 ABCB5 基因敲除 PD-L1 Ig 给药和 ABCB5+ 干细胞植入背景下的谱系追踪模型。这 基本原理是，成功完成这项工作后，我们将确定新的治疗方法 通过皮肤操作治疗和预防aGVHD皮肤和鳞状粘膜病理学 内在免疫抑制途径。